Hypoxic Ventilatory Response Test Research Articles

Using modified Fenn diagrams to assess ventilatory acclimatization during ascent to high altitude: Effect of acetazolamide.

High altitude (HA) ascent imposes systemic hypoxia and associated risk of acute mountain sickness. Acute hypoxia elicits a hypoxic ventilatory response (HVR), which is augmented with chronic HA exposure (i.e., ventilatory acclimatization; VA). However, laboratory-based HVR tests lack portability and feasibility in field studies. As an alternative, we aimed to characterize area under the curve (AUC) calculations on Fenn diagrams, modified by plotting portable measurements of end-tidal carbon dioxide ( ) against peripheral oxygen saturation ( ) to characterize and quantify VA during incremental ascent to HA (n=46). Secondarily, these participants were compared with a separate group following the identical ascent profile whilst self-administering a prophylactic oral dose of acetazolamide (Az; 125mg BID; n=20) during ascent. First, morning and measurements were collected on 46 acetazolamide-free (NAz) lowland participants during an incremental ascent over 10days to 5160m in the Nepal Himalaya. AUC was calculated from individually constructed Fenn diagrams, with a trichotomized split on ranked values characterizing the smallest, medium, and largest magnitudes of AUC, representing high (n=15), moderate (n=16), and low (n=15) degrees of acclimatization. After characterizing the range of response magnitudes, we further demonstrated that AUC magnitudes were significantly smaller in the Az group compared to the NAz group (P=0.0021), suggesting improved VA. These results suggest that calculating AUC on modified Fenn diagrams has utility in assessing VA in large groups of trekkers during incremental ascent to HA, due to the associated portability and congruency with known physiology, although this novel analytical method requires further validation in controlled experiments. HIGHLIGHTS: What is the central question of this study? What are the characteristics of a novel methodological approach to assess ventilatory acclimatization (VA) with incremental ascent to high altitude (HA)? What is the main finding and its importance? Area under the curve (AUC) magnitudes calculated from modified Fenn diagrams were significantly smaller in trekkers taking an oral prophylactic dose of acetazolamide compared to an acetazolamide-free group, suggesting improved VA. During incremental HA ascent, quantifying AUC using modified Fenn diagrams is feasible to assess VA in large groups of trekkers with ascent, although this novel analytical method requires further validation in controlled experiments.

Ventilatory Responsiveness during Exercise and Performance Impairment in Acute Hypoxia.

An adequate increase in minute ventilation to defend arterial oxyhemoglobin saturation (SpO2) during hypoxic exercise is commonly viewed as an important factor contributing to large inter-individual variations in the degree of exercise performance impairment in hypoxia. Although the hypoxic ventilatory response (HVR) could provide insight into the underpinnings of such impairments, it is typically measured at rest under isocapnic conditions. Thus, we aimed to determine whether 1) HVR at rest and during exercise are similar and 2) exercise HVR is related to the degree of impairment in cycling time trial (TT) performance from normoxia to acute hypoxia (∆TT). Sixteen endurance-trained men (V˙O2peak, 62.5 ± 5.8 mL·kg-1·min-1) performed two poikilocapnic HVR tests: one during seated rest (HVRREST) and another during submaximal cycling (HVREX). On two separate visits, subjects (n = 12) performed a 10-km cycling TT while breathing either room air (FiO2 = 0.21) or hypoxic gas mixture (FiO2 = 0.16) in a randomized order. HVREX was significantly (P < 0.001) greater than HVRREST (1.52 ± 0.47 and 0.22 ± 0.13 L·min-1·%SpO2-1, respectively), and these measures were not correlated (r = -0.16, P = 0.57). ∆TT was not correlated with HVRREST (P = 0.70) or HVREX (P = 0.54), but differences in ventilation and end-tidal CO2 between hypoxic and normoxic TT and the ventilatory equivalent for CO2 during normoxic TT explained ~85% of the variance in performance impairment in acute hypoxia (P < 0.01). We conclude that 1) HVR is not an appropriate measure to predict the exercise ventilatory response or performance impairments in acute hypoxia and 2) an adequate and metabolically matched increase in exercise ventilation, but not the gain in the ventilatory response to hypoxia, is essential for mitigating hypoxia-induced impairments in endurance cycling performance.

Exercise Overrides Blunted Hypoxic Ventilatory Response in Prematurely Born Men.

PurposePre-term birth provokes life-long anatomical and functional respiratory system sequelae. Although blunted hypoxic ventilatory response (HVR) is consistently observed in pre-term infants, it remains unclear if it persists with aging and, moreover, if it influences hypoxic exercise capacity. In addition, it remains unresolved whether the previously observed prematurity-related alterations in redox balance could contribute to HVR modulation.MethodsTwenty-one prematurely born adult males (gestational age = 29 ± 4 weeks], and 14 age matched controls born at full term (gestational age = 39 ± 2 weeks) underwent three tests in a randomized manner: (1) hypoxia chemo-sensitivity test to determine the resting and exercise poikilocapnic HVR and a graded exercise test to volitional exhaustion in (2) normoxia (FiO2 = 0.21), and (3) normobaric hypoxia (FiO2 = 0.13) to compare the hypoxia-related effects on maximal aerobic power (MAP). Selected prooxidant and antioxidant markers were analyzed from venous samples obtained before and after the HVR tests.ResultsResting HVR was lower in the pre-term (0.21 ± 0.21 L ⋅ min-1 ⋅ kg-1) compared to full-term born individuals (0.47 ± 0.23 L ⋅ min-1 ⋅ kg-1; p < 0.05). No differences were noted in the exercise HVR or in any of the measured oxidative stress markers before or after the HVR test. Hypoxia-related reduction of MAP was comparable between the groups.ConclusionThese findings indicate that blunted resting HVR in prematurely born men persists into adulthood. Also, active adults born prematurely seem to tolerate hypoxic exercise well and should, hence, not be discouraged to engage in physical activities in hypoxic environments. Nevertheless, the blunted resting HVR and greater desaturation observed in the pre-term born individuals warrant caution especially during prolonged hypoxic exposures.

Acute mountain sickness, chemosensitivity, and cardiorespiratory responses in humans exposed to hypobaric and normobaric hypoxia

We examined the control of breathing, cardiorespiratory effects, and the incidence of acute mountain sickness (AMS) in humans exposed to hypobaric hypoxia (HH) and normobaric hypoxia (NH), and under two control conditions [hypobaric normoxia (HN) and normobaric normoxia (NN)]. Exposures were 6 h in duration, and separated by 2 wk between hypoxic exposures and 1 wk between normoxic exposures. Before and after exposures, subjects (n = 11) underwent hyperoxic and hypoxic Duffin CO2 rebreathing tests and a hypoxic ventilatory response test (HVR). Inside the environmental chamber, minute ventilation (V(E)), tidal volume (V(T)), frequency of breathing (fB), blood oxygenation, heart rate, and blood pressure were measured at 5 and 30 min and hourly until exit. Symptoms of AMS were evaluated using the Lake Louise score (LLS). Both the hyperoxic and hypoxic CO2 thresholds were lower after HH and NH, whereas CO2 sensitivity was increased after HH and NH in the hypoxic test and after NH in the hyperoxic test. Values for HVR were similar across the four exposures. No major differences were observed for Ve or any other cardiorespiratory variables between NH and HH. The LLS was greater in AMS-susceptible than in AMS-resistant subjects; however, LLS was alike between HH and NH. In AMS-susceptible subjects, fB correlated positively and Vt negatively with the LLS. We conclude that 6 h of hypoxic exposure is sufficient to lower the peripheral and central CO2 threshold but does not induce differences in cardiorespiratory variables or AMS incidence between HH and NH.

Sleep quality under mild hypoxia in men with low hypoxic ventilatory response

The present study evaluated whether slow-wave sleep and whole-night delta power of the non-rapid eye movement (NREM) sleep electroencephalogram (EEG) decrease during sleep at a simulated altitude of 2000 m, and whether such changes related to measures of hypoxic ventilatory response (HVR). This study consisted of two parts; in the first, HVR was measured in 41 subjects and each seven subjects with the lowest or the highest HVR were selected for the subsequent sleep study. In the second part, polysomnogram, arterial oxygen saturation (SpO2) and respiratory events are recorded on the selected subjects under normoxic and hypoxic conditions. Hypoxia decreased SpO2 and increased respiratory disturbances for both groups. The low HVR group, but not the high HVR group, showed decreases in the whole-night delta power of NREM sleep EEG under hypoxia. On the other hand, two subjects in the high HVR group, who showed relatively high apnoea indices, also showed lower SpO2 nadirs and decreases in the whole-night delta power under hypoxia. These results suggest that acute hypoxia equivalent to that at a 2000 m altitude decreases slow-wave sleep in individuals that show low HVR. However, low HVR may not be the only, but one of some factors that decrease the whole-night delta power under hypoxia. Therefore, it was not sufficient to identify individuals likely to be susceptible to deteriorated sleep quality at a simulated altitude of 2000 m only using the HVR test. Other factors, which relate to respiratory instabilities, should be taken into consideration to identify them.

Volatile organic compounds (VOCs) in exhaled breath condensate (EBC) as a biomarker of high altitude pulmonary edema (HAPE)

HAPE is the most common cause of death at high altitude. The underlying pathophysiology of HAPE is not well understood. While certain individuals are more susceptible to developing HAPE, the ability to identify these individuals prior to ascent has yet to be determined. The present study was designed to determine if a difference exists between the profile of VOCs in EBC, hypoxic ventilatory response (HVR) and pulmonary artery systolic pressures (PASP) in healthy males with (HAPE, n=5) and without (control, n=11) a history of HAPE. On the first day of the protocol, subjects performed pulmonary function, VO2 max, and HVR tests. On the second day of the study, the subjects completed a pre and post hypoxic exposure 20 minute EBC collection, supine exercise test with Doppler Echocardiography measurement of PASP and a ninety minute hypoxic exposure (12% O2) with measurement of PASP. The main results of the study showed that the EBC profile of VOCs was significantly different between groups. In addition, this profile was strongly correlated with HVR. These results indicate that EBC analysis can be used to identify individuals who have had a previous episode of HAPE, as well as physiological responses to hypoxia. In the future, this technique could be used in the field to determine HAPE sensitivity prior to altitude exposure.

Performance of a compact end-tidal forcing system

The purpose of the present study was to develop and validate a new compact, portable end-tidal forcing (ETF) system capable of reliably controlling end-tidal gases. The system consists of compressed gas sources (air, N(2) and CO(2)) that are connected via three solenoid valves to a humidification chamber and an inspiratory reservoir bag from which the participant breathes. This computer-controlled system compares actual end-tidal gas partial pressures with target pressures and mixes the gases on a breath-by-breath basis. This leaves no unused exhaust gas and keeps gas requirements to a minimum. Eight participants underwent two different 30-min protocols that included each possible combination of end-tidal O(2) partial pressure (PET O2) and end-tidal CO(2) partial pressure (PET O2) control at two different levels (PET O2 at 55 and 75 mmHg; and PET CO2 at 4 and 7 mmHg above resting). The ETF system maintained the mean PET CO2 at 0.13 mmHg from the target values, with a pooled S.D. across conditions of +/-0.91 mmHg and a 95% confidence interval (CI) of +/-0.63 mmHg. The mean PET CO2 was held at 0.49 mmHg from its target values, with a pooled S.D. across conditions of +/-1.31 mmHg and a 95% CI of +/-0.91 mmHg. To demonstrate suitability of this system for measuring chemosensitivity to hypoxia, hypoxic ventilatory response (HVR) tests were conducted in a subset of five participants. During a 20-min HVR test both PET CO2 and PET O2 were not significantly different from their target values. These data demonstrate the performance of a portable, compact, economical system that controls PET CO2 within 1 mmHg and PET O2 within 2 mmHg of their respective target values.

Repeated measurement of hypoxic ventilatory response as an intermittent hypoxic stimulus

Measurement of hypoxic ventilatory response (HVR) involves an exposure to hypoxia which, if repeated over several days might act as an intermittent hypoxic stimulus. The purpose of this study was to measure HVR repeatedly over 5 days to determine whether it was affected by repeated measurement. Nine healthy male subjects completed an isocapnic HVR test, on one occasion, followed 5 days later by one measurement each day for 5 days. Each test lasted approximately 5-8 min with inspired oxygen concentration declining to as a low as 5-6%. No systematic trend was observed in HVR over the 5-day period (p>0.05). There were no significant differences in HVR between any of the test days. Regression failed to show any trend in HVR over the five sequential days. The calculated mean coefficient of variation for HVR for each subject was 27%. There is no evidence that the short exposure to hypoxia as part of HVR measurement is a co-intervention when measured repeatedly over 5 days in physiological studies.

Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes.

This study determined whether "living high-training low" (LHTL)-simulated altitude exposure increased the hypoxic ventilatory response (HVR) in well-trained endurance athletes. Thirty-three cyclists/triathletes were divided into three groups: 20 consecutive nights of hypoxic exposure (LHTLc, n = 12), 20 nights of intermittent hypoxic exposure (four 5-night blocks of hypoxia, each interspersed with 2 nights of normoxia, LHTLi, n = 10), or control (Con, n = 11). LHTLc and LHTLi slept 8-10 h/day overnight in normobaric hypoxia (approximately 2,650 m); Con slept under ambient conditions (600 m). Resting, isocapnic HVR (DeltaVE/DeltaSp(O(2)), where VE is minute ventilation and Sp(O(2)) is blood O(2) saturation) was measured in normoxia before hypoxia (Pre), after 1, 3, 10, and 15 nights of exposure (N1, N3, N10, and N15, respectively), and 2 nights after the exposure night 20 (Post). Before each HVR test, end-tidal PCO(2) (PET(CO(2))) and VE were measured during room air breathing at rest. HVR (l. min(-1). %(-1)) was higher (P < 0.05) in LHTLc than in Con at N1 (0.56 +/- 0.32 vs. 0.28 +/- 0.16), N3 (0.69 +/- 0.30 vs. 0.36 +/- 0.24), N10 (0.79 +/- 0.36 vs. 0.34 +/- 0.14), N15 (1.00 +/- 0.38 vs. 0.36 +/- 0.23), and Post (0.79 +/- 0.37 vs. 0.36 +/- 0.26). HVR at N15 was higher (P < 0.05) in LHTLi (0.67 +/- 0.33) than in Con and in LHTLc than in LHTLi. PET(CO(2)) was depressed in LHTLc and LHTLi compared with Con at all points after hypoxia (P < 0.05). No significant differences were observed for VE at any point. We conclude that LHTL increases HVR in endurance athletes in a time-dependent manner and decreases PET(CO(2)) in normoxia, without change in VE. Thus endurance athletes sleeping in mild hypoxia may experience changes to the respiratory control system.

Cardiac Asystole During an Hypoxic Drive Study in a Normal Subject

A healthy 31-year-old man who had previously sojourned to an altitude of 5,000 meters with no detrimental effect developed sudden cardiac asystole during a progressive hypoxic ventilatory response ( HVR ) test. At the moment of asystole, his alveolar PO2 (PAO2) was 41 mm Hg and his arterial oxygen saturation (SaO2) was 81 percent. Cardiopulmonary resuscitation was initiated, and after 20 seconds of asystole and apnea, he recovered normal sinus rhythm and spontaneous respiration. A subsequent ECG and cardiac enzyme levels were normal. During testing, he demonstrated depressed ventilation in response to hypoxia and a slowing of the heart rate. Careful observation of heart rate and breath-by-breath ventilation during HVR tests may predict this potentially fatal complication.